Serotonin SSRIs?

 Serotonin Study Notes

Basic Identity

• Serotonin is also called 5-hydroxytryptamine (5-HT).

• It is derived from tryptophan.

• Synthesized and secreted by nerve endings (especially in the brain), the gut, and platelets.

• In platelets, serotonin is stored in dense (delta) granules.

Name origin:

• Called serotonin because it is found in the serum.

• Biochemical steps:

  • Tryptophan → 5-hydroxytryptophan (via tryptophan hydroxylase).

  • 5-hydroxytryptophan → serotonin (via aromatic amino acid decarboxylase).

Termination of Action

• After release, serotonin is removed in two ways:

  • Reuptake by the serotonin transporter (SERT).

  • Metabolism by monoamine oxidase (MAO-A).

• Selective Serotonin Reuptake Inhibitors (SSRIs): block reuptake.

• MAO enzymes:

  • MAO-A: metabolizes norepinephrine, epinephrine, serotonin, dopamine, tyramine (found in liver, neurons, GI tract).

  • MAO-B: metabolizes dopamine (found in brain and platelets).

  • Phenelzine and tranylcypromine: inhibit both MAO-A and B → used for depression.

  • Selegiline: selective MAO-B inhibitor → used in Parkinson’s disease.

Serotonin Receptors

• Largest known neurotransmitter receptor family.

• Main subtypes: 5-HT1 to 5-HT7.

Coupling:

• 5-HT1 → Gi (subtypes 1A, 1B, 1C, 1D).

• 5-HT2 → Gq (subtypes 2A, 2B, 2C).

• 5-HT3 → ligand-gated sodium/potassium channel.

• 5-HT4, 5-HT6, 5-HT7 → Gs.

• 5-HT5 → Gi (subtypes 5A, 5B).

Functions:

• 5-HT2A → sexual dysfunction (anorgasmia).

• 5-HT2C → weight gain (“see these fat rolls”).

• 5-HT3 → vomiting (“vomit on three”).

Clinical Applications

Depression and Anxiety

• Biogenic amine hypothesis: low norepinephrine, serotonin, and dopamine → depression.

• SSRIs: increase serotonin in the synapse.

• Used for depression, OCD, GAD, PTSD, panic disorder, bulimia.

• Side effects: agitation, anxiety, nausea, vomiting, weight gain, sexual dysfunction, bleeding risk, serotonin syndrome.

• Don’t combine with aspirin, warfarin, or MAOIs.

Serotonin Syndrome

• Cause: SSRI overdose, drug interactions, carcinoid tumor.

• Symptoms: rigidity, hyperthermia, flushing, myoclonus, autonomic instability, diarrhea, confusion, coma, death.

• Treatment: supportive (ABC), benzodiazepines, cyproheptadine (serotonin antagonist).

Carcinoid Syndrome

• Serotonin-secreting tumor (GI tract, bronchus).

• Diagnosis: ↑ serotonin, ↑ 5-HIAA (5-hydroxyindoleacetic acid) in serum/urine.

• Symptoms: diarrhea, flushing, bronchospasm, right-sided heart disease (pulmonic stenosis, tricuspid regurgitation).

• Treatment: octreotide (somatostatin analog), cyproheptadine.

Chemotherapy-related Vomiting

• 5-HT3 antagonists (e.g., ondansetron) prevent nausea/vomiting, especially in chemo.

• “We vomit on three.”

Key Drugs Affecting Serotonin

• SSRIs: block serotonin reuptake (first-line for depression/anxiety).

• Bupropion: increases dopamine and norepinephrine release, used for depression and smoking cessation.

• Buspirone: partial agonist at 5-HT1A, used for anxiety.

• Atypical antipsychotics: block 5-HT2A (used for schizophrenia, depression). Can prolong QT.

• Hydroxyzine: antihistamine, also blocks serotonin (used for anxiety).

• Cyproheptadine: antihistamine, serotonin antagonist (used for serotonin syndrome, carcinoid syndrome).

• Lorcaserin: 5-HT2C agonist, weight loss drug (satiety center in hypothalamus).

• Sumatriptan: 5-HT1B/1D agonist, used for migraine.

• Ergotamine, Methysergide: partial 5-HT agonists/antagonists for migraine.

GI and Other Roles

• In the gut, serotonin promotes peristalsis via the myenteric plexus.

• Excess serotonin → secretory diarrhea, cramps, flushing, bronchospasm.

• Serotonin can be further metabolized to melatonin in the pineal gland.